Identification of [1,2,4]Triazolo[4,3-a]pyrazine PARP1 inhibitors with overcome acquired resistance activities.

Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors can selectively kill homologous recombination (HR) deficient cancer cells and elicit anticancer effect through a mechanism of synthetic lethality. In this study, we designed, synthesized and pharmacologically evaluated a series of [1,2,4]triazolo[4,3- a ]pyrazine derivatives as a class of potent PARP1 inhibitors. Among them, compounds 17m , 19a , 19c , 19e , 19i and 19k not only displayed more potent inhibitory activities (IC 50 s < 4.1 nM) than 9 and 1 against PARP1, but also exhibited nanomolar range of antiproliferative effects against MDA-MB-436 (BRCA1−/−, IC 50 s < 1.9 nM) and Capan-1 (BRCA2−/−, IC 50 s < 21.6 nM) cells. Notably, 19k significantly inhibited proliferation of resistant Capan-1 cells (IC 50 s < 0.3 nM). Collectively, the newly discovered PARP1 inhibitors act as a useful pharmacological tool for investigating the mechanism of acquired resistance to PARP1 inhibitors, and may also represent promising therapeutic agents for the treatment of HR deficient cancers with the potential to overcome the acquired resistance. [Display omitted] • Several series of [1,2,4]triazolo[4,3-a]pyrazine derivatives have been designed and synthesized. • 17m, 19a, 19i and 19k are identified as potent and novel PARP1 inhibitors. • 19k exhibited potent antiproliferative effects against BRCA-mutated cells. • 19k showed promising antiproliferative efficacy against PARP1 inhibitor-resistant cells. [ABSTRACT FROM AUTHOR]